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Abstract:

Pharmaceutical compositions, including unit dosage forms, comprising fine
particle abiraterone acetate with or without an antioxidant and or a
sequestering agent as well as methods for producing and using such
compositions are described.

Claims:

1. A method for producing a composition comprising nanoparticles of
abiraterone acetate, the method comprising: dry milling a composition
comprising abiraterone acetate, a millable grinding compound, a
facilitating agent and one or both of an antioxidant and a sequestering
agent in a mill comprising a plurality of milling bodies, for a time
period sufficient to produce a composition comprising fine particles of
the abiraterone acetate, wherein the particle size of the grinding matrix
and the particle size of the abiraterone acetate is reduced by dry
milling.

3. The method of claim 1, wherein the milling takes place in the presence
of one or both of an antioxidant and a sequestering agent.

4. The method of claim 3, wherein the antioxidant is selected from
ascorbic acid, BHA and BHT.

5. The method of claim 3, wherein the sequestering agent is selected from
fumaric acid, tartartic acid and citric acid.

6. The method of claim 1, wherein the [D50] of the fin particles of
abiraterone acetate in the composition comprising fine particles of
abiraterone acetate is less than 600 nm, less than 500 nm, less than 400
nm, less than 300 nm.

7. The method of claim 1, wherein the [D4,3] of the fine particles
of abiraterone acetate in the composition comprising fine particles of
abiraterone acetate is greater than 100 nm and less than one of: 700 nm,
600 nm, 500 nm, 400 nm, and 300 nm.

8. A method for preparing a unit dosage composition comprising: preparing
a composition comprising fine particles of abiraterone acetate according
to the method of claim 1, combining the composition comprising fine
particles of abiraterone acetate with one or more pharmaceutically
acceptable diluents, disintegrants, lubricants, glidants or dispersants.

9. The method of claim 8, wherein the unit dosage composition is a tablet
or capsule.

11. The method of claim 10, wherein the dissolution rate of the
abiraterone acetate in the unit dosage composition is such that when a
sample containing 100 mg of abiraterone acetate is tested in 900 ml of pH
4.5 phosphate buffer (0.1% SLS) using USP Apparatus II at 75 rpm, at
least 80% of the abiraterone acetate dissolves in 15 min or less or in 10
min or less.

12. The method of claim 10 or 11, wherein the unit dosage composition is
a tablet and the dissolution rate is such that when the tablet is tested
in 900 ml of pH 4.5 phosphate buffer (0.1% SLS) using USP Apparatus II at
75 rpm, at least 90% of the abiraterone acetate dissolves in either 15
min or less or in 10 min or less.

[0002] The present disclosure relates to methods for producing particles
of abiraterone acetate using dry milling processes as well as
compositions comprising abiraterone acetate, medicaments produced using
abiraterone acetate and to methods of treatment using a therapeutically
effective amount of abiraterone acetate administered by way of said
medicaments.

BACKGROUND

[0003] Poor oral bioavailability is a significant problem encountered in
the development of therapeutic compositions, particularly those
compositions containing a drug which is poorly soluble in water at
physiological pH. A drug's oral bioavailability is the degree to which
the drug is absorbed into the bloodstream after oral administration. Many
factors affect oral bioavailability, including the form of dosage and the
solubility and dissolution rate of the drug.

[0004] In therapeutic applications, poorly water-soluble drugs tend to be
eliminated from the gastrointestinal tract before being completely
absorbed into the circulation. They also tend to be absorbed slowly,
which can result in slow onset of therapeutic effect. In addition, poorly
water-soluble drugs tend to be disfavored or even unsafe for intravenous
administration due to the risk of particles of drug blocking blood flow
through capillaries.

[0005] It is known that increasing the rate of dissolution of poorly
soluble drugs will, in many cases, increase the rate and extent of their
oral absorption. It is also known that the rate of dissolution of a
particulate drug will increase with increasing surface area. One way of
increasing surface area is decreasing particle size. Consequently,
methods of making finely divided or sized drugs have been studied with a
view to increasing the surface area and dissolution rates of drug
particles used in pharmaceutical compositions.

[0006] Abiraterone ((3β)-17-(pyridin-3-yl) androsta-5, 16-dien-3-ol;
CAS #: 154229-19-3; Formula: C24H31NO; Mol. Weight: 349.5
g/mol) is an inhibitor of CYP17 and thus interferes with the synthesis of
androgens in the testes, adrenal glands and prostate tumor tissue.
Abiraterone acetate (17-(3-Pyridyl)androsta-5, acetate; CAS
#154229-18-2), a prodrug of abiraterone, is approved in the United States
for treatment of castration-resistant prostate cancer. Abiraterone
acetate is considered poorly water soluble.

[0007] Zytiga® Tablets (250 mg) are approved in the United States in
combination with prednisone for the treatment of patients with metastatic
castration-resistant prostate cancer. The prescribing information for
Zytiga® tablets recommends 1,000 mg (4×250 mg tablets)
administered orally once daily in combination with prednisone (5 mg)
administered orally twice daily. The European approval is for
administration in combination with either prednisone or prednisolone. The
prescribing information states that Zytiga® must be taken on an empty
stomach and that no food should be consumed for at least two hours before
the dose is taken and for and for at least one hour after the dose is
taken. The prescribing information explains that at a dose of 1,000 mg
daily in patients with metastatic, castration resistant prostate cancer
the steady-state values (mean±SD) of Cmax were 226±178 ng/mL and of
AUC were 1173±690 nghr/mL. A single dose (1000 mg) cross-over study of
Zytiga in healthy subjects found that systemic exposure of abiraterone is
increased when Zytgia® is administered with food. Specifically,
abiraterone Cmax and AUC0-∞ were approximately 7- and
5-fold higher, respectively, when Zytiga® was administered with a
low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold
higher, respectively, when Zytiga® was administered with a high-fat
(57% fat, 825 calories) meal.

SUMMARY

[0008] The present disclosure features pharmaceutical compositions,
including unit dosage forms, comprising fine particle abiraterone acetate
as well as methods for producing and using such compositions.

[0010] In the various embodiments described herein the [D90] is less than
1000 nm or less than 900 nm. In some embodiments the [D90] is 1000
nm-600 nm, 900 nm-600 nm, 900 nm-700 nm or 900 nm and 800 nm.

[0011] In another embodiment, the crystallinity profile of the abiraterone
acetate is selected from the group consisting of: at least 50% of the
abiraterone acetate is crystalline, at least 60% of the abiraterone
acetate is crystalline, at least 70% of the abiraterone acetate is
crystalline, at least 75% of the abiraterone acetate is crystalline, at
least 85% of the abiraterone acetate is crystalline, at least 90% of the
abiraterone acetate is crystalline, at least 95% of the abiraterone
acetate is crystalline and at least 98% of the abiraterone acetate is
crystalline. In some embodiments, the crystallinity profile of the
abiraterone acetate is substantially equal to the crystallinity profile
of the abiraterone acetate before the material was subjected to the
method as described herein.

[0012] In another embodiment, the amorphous content of the abiraterone
acetate is selected from the group consisting of: less than 50% of the
abiraterone acetate is amorphous, less than 40% of the abiraterone
acetate is amorphous, less than 30% of the abiraterone acetate is
amorphous, less than 25% of the abiraterone acetate is amorphous, less
than 15% of the abiraterone acetate is amorphous, less than 10% of the
abiraterone acetate is amorphous, less than 5% of the abiraterone acetate
is amorphous and less than 2% of the abiraterone acetate is amorphous. In
some embodiments, the abiraterone acetate has no significant increase in
amorphous content after subjecting the material to the dry milling method
described herein.

[0013] In some embodiments, the nanoparticles of abiraterone acetate are
prepared by dry milling abiraterone acetate with a millable grinding
compound and a facilitating agent. Additional components can be present
during the milling and together the various components present during
milling (with the exception of abiraterone acetate and the milling
bodies) are referred to as a grinding matrix. The milling produces
particles of abiraterone acetate that are significantly reduced in size
dispersed in grinding matrix. Because all of the components in the
grinding matrix are pharmaceutically acceptable, pharmaceutical
compositions can be prepared using the mixture of abiraterone acetate and
grinding matrix produced by the milling. In some cases additional
pharmaceutically acceptable components can be added to the mixture of
abiraterone acetate and grinding matrix. In some embodiments the dry
milling takes place in the presence of milling bodies.

[0014] In some cases abiraterone acetate is milled with one or more
millable grinding compounds selected from: lactose (e.g., lactose
monohydrate or lactose anhydrous) and mannitol and one or more
facilitating agents selected from sodium lauryl sulfate and povidone. In
some cases abiraterone acetate is milled with lactose (e.g., lactose
monohydrate) and sodium lauryl sulfate. In some cases during dry milling
the abiraterone acetate can be present at 20-60% (w/w) the lactose at up
to 80% (w/w) the mannitol at up to 80% (w/w) and the povidone and sodium
lauryl sulfate each (or both) at 1-3% (w/w).

[0015] In some embodiments, the abiraterone acetate is dry milled in the
presence of one or more antioxidants and/or one or more sequestering
agents (i.e., an agent that can sequester ions, e.g, metal ions) in
addition to at least one millable grinding compound and at least one
facilitating agent. Thus, one or more of: butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), ascorbic acid, fumaric acid, tartaric
acid and citric acid (e.g, anhydrous citric acid) or mixtures thereof can
be present during the dry milling. In some cases, both at least one
antioxidant and at least one sequestering agent are present during
milling. During milling, the ascorbic acid, fumaric acid, tartaric acid
and citric acid (e.g, anhydrous citric acid) can be present at 8% or less
on a w/w basis (e.g, 5%-0.1%, 1%-0.1%, or 0.2% each or in combination)
and the BHT and BHA can be present at 0.5% or less (e.g., 0.5%-0.01%,
0.1%-0.08%, 0.08%-0.04%, or 0.05% each or in combination). One or more
additional antioxidants and/or one or more additional sequestering agents
can be added to the milled material after milling is completed.

[0017] Also described herein is a method for treating a patient comprising
administering a daily dose of 900 mg to 50 mg of abiraterone acetate
(e.g, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300,
250, 225, 200, 150, 100, 90, 80, 70, 60, 50 mg) in the form of a
pharmaceutical composition described herein (e.g, by administering one or
more units of a unit dosage form described herein comprising abiraterone
acetate). The patient can also be treated with a glucocorticoid such as
prednisone, prednisolone, or dexamethasone. Alternatively, the patient
can be treated with methylprednisolone (e,g., at 100 mg/day)

[0018] In some cases, for the dosage forms described herein, the
AUC0-∞ for a single dose of a dosage form described herein
when administered with a low-fat meal (7% fat, 300 calories) is 4-fold or
less (3-fold or less, 2-fold or less, 1.5-fold or less) higher than when
administered in the fasted state.

[0019] In some cases, for the dosage forms described herein, the
AUC0-∞ for a single dose of a dosage form described herein
when administered with a high-fat meal (57% fat, 825 calories) is 8-fold
or less (7-fold or less, 5-fold or less, 3-fold or less, 2-fold or less,
1.5-fold or less) higher than when administered in the fasted state.

[0020] In some cases, for the dosage forms described herein, the variation
in Cmax for a single dose of a dosage form described herein when
administered with a low-fat meal (7% fat, 300 calories) is 6-fold or less
(5-fold or less or 4-fold or less, 3-fold or less, 2-fold or less,
1.5-fold or less) higher than when administered in the fasted state.

[0021] In some cases, for a single dose of a dosage form described herein,
the variation in Cmax when administered with a high-fat meal (57% fat,
825 calories) is 15-fold or less (13-fold or less, 11-fold or less,
9-fold or less or 7-fold or less, 5-fold or less, 3-fold or less, 2-fold
or less, 1.5-fold or less) higher than when administered in the fasted
state.

[0022] The dissolution rate of a tablet containing 100 mg of abiraterone
acetate (or a 100 mg of abiraterone acetate portion of a tablet
containing more than 100 mg of abiraterone acetate, e.g., half of a 200
mg containing tablet), when tested in 900 ml of pH 4.5 phosphate buffer
(0.1% SLS) using USP Apparatus II at 75 rpm is such that at least 90% or
at least 95% of the abiraterone acetate dissolves in 20 min or less (e.g,
19 min or less, 18 min or less, 17 min or less, 16 min or less, 15 min or
less, 14 min or less, 13 min or less, 11 min or less, 9 min or less). In
cases where the tablet contains more or less than 100 mg of abiraterone
acetate the dissolution rate given is for a fraction of a larger tablet
(or multiple of a smaller tablet) providing 100 mg of abiraterone
acetate).

[0023] In some cases, at least 90% or at least 95% of the abiraterone
acetate dissolves in 20 min or less (e.g, 19 min or less, 18 min or less,
17 min or less, 16 min or less, 15 min or less, 14 min or less, 13 min or
less, 11 min or less, 9 min or less) after storage at 4 weeks or more
(e.g., 8 weeks or 12 weeks) at 25° C. at 60% RH. In some cases, at
least 95% of the abiraterone acetate dissolves in 15 min or less (e.g, 14
min or less, 13 min or less, 11 min or less, 9 min or less) after storage
at 3 weeks or more (e.g., 6 weeks or 9 weeks) at 40° C. at 75% RH.
Here too, in cases where the tablet contains more or less than 100 mg of
abiraterone acetate the dissolution rate given is for a fraction of a
larger tablet (or multiple of a smaller tablet) providing 100 mg of
abiraterone acetate).

[0024] In certain embodiments, in comparative pharmacokinetic testing with
Zytiga®, an abiraterone acetate composition of the disclosure
exhibits less variability than the conventional composition. Thus, in
some embodiments, the coefficient of variation observed for a
pharmaceutical composition described herein in one or more of Cmax,
AUC(0-t), and AUC(0-∞) will be less than 50%, less than 40%, less
than 30%, less than 25%, or less than 20%. In some embodiments, a
pharmaceutical composition described herein shows less variability in the
average plasma concentration at any given time point after administration
relative to e.g., Zytiga®.

[0025] In some cases, the hardness of abiraterone tablets is between 100N
and 170N (e.g., 110N to 160N).

[0026] In some embodiments, the dry milling apparatus is a mill selected
from the group consisting of: attritor mills (horizontal or vertical),
nutating mills, tower mills, pearl mills, planetary mills, vibratory
mills, eccentric vibratory mills, gravity-dependent-type ball mills, rod
mills, roller mills and crusher mills. In some embodiments, the milling
bodies within the milling apparatus are mechanically agitated by 1, 2 or
3 rotating shafts. Preferably, the method is configured to produce the
abiraterone acetate in a continuous fashion. The milling bodies can be
formed of a material selected from the group consisting of: ceramics,
glasses, steels, polymers, ferromagnetics and metals and other suitable
materials. In some embodiments, the milling bodies are steel balls having
a diameter selected from the group consisting of: between 1 and 20 mm,
between 2 and 15 mm and between 3 and 10 mm. In various embodiments of
the dry milling method, the milling bodies are zirconium oxide balls
having a diameter selected from the group consisting of: between 1 and 20
mm, between 2 and 15 mm and between 3 and 10 mm. In another embodiment,
the milling time period is a range selected from the group consisting of:
between 10 minutes and 2 hours, between 10 minutes and 90 minutes,
between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between
10 minutes and 30 minutes, between 5 minutes and 30 minutes, between 5
minutes and 20 minutes, between 2 minutes and 10 minutes, between 2
minutes and 5 minutes, between 1 minutes and 2

[0028] In some embodiments, the concentration of the single (or first)
grinding matrix is selected from the group consisting of: 5-99% w/w,
10-95% w/w, 15-85% w/w, of 20-80% w/w, 25-75% w/w, 30-60% w/w, 40-50%
w/w. In some embodiments, the concentration of the second or subsequent
grinding matrix is selected from the group consisting of: 5-50% w/w,
5-40% w/w, 5-30% w/w, of 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w,
20-40% w/w, or 20-30% w/w or if the second or subsequent material is a
surfactant or water soluble polymer the concentration is selected from
0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w,
0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1%
and 1% w/w.

[0029] In some embodiments, abiraterone acetate is milled in the presence
of:

[0041] In some embodiments, the abiraterone acetate is dry milled with one
or more additional materials is selected from the group consisting of: a
material considered to be `Generally Regarded as Safe` (GRAS) for
pharmaceutical products.

[0046] In some embodiments, a facilitating agent is used or combination of
facilitating agents is used during dry milling. In some embodiments, the
facilitating agent is added during dry milling. In some embodiments, the
facilitating agent is added to the dry milling at a time selected from
the group consisting of: with 1-5% of the total milling time remaining,
with 1-10% of the total milling time remaining, with 1-20% of the total
milling time remaining, with 1-30% of the total milling time remaining,
with 2-5% of the total milling time remaining, with 2-10% of the total
milling time remaining, with 5-20% of the total milling time remaining
and with 5-20% of the total milling time remaining.

[0048] In another aspect the disclosure includes a method of treating a
human in need of such treatment comprising the step of administering to
the human an effective amount of a pharmaceutical composition as
described herein for treatment of castration resistant prostate cancer.
The patient can also be treated with a glucocorticoid, e.g, predisone,
dexamethasone or prednisolone (e.g., at 5 mg, twice daily).
Alternatively, the patient can be treated with methylprednisolone. The
patient can also be treated with other chemotherapeutic agents or other
agents for the treatment of cancer (e.g., prostate cancer).

[0049] The disclosure also includes a method for treating breast cancer
(e.g., metastatic breast cancer) and ovarian cancer (e.g., epithelial
ovarian cancer) using a composition described herein.

[0050] In another aspect, the disclosure comprises the use of a
pharmaceutical composition as described herein in the manufacture of a
medicament for the treatment of a human in need of such treatment.

[0051] In another aspect the disclosure comprises a method for
manufacturing a pharmaceutical composition as described herein comprising
the step of combining a therapeutically effective amount of a composition
comprising abiraterone acetate prepared by a method described herein or a
composition as described herein, together with one of a diluent,
lubricant, excipient, disintegrant, wetting agent, and carrier, to
produce a pharmaceutically acceptable dosage form.

[0052] Those skilled in the art will appreciate that the disclosure
described herein is susceptible to variations and modifications other
than those specifically described. It is to be understood that the
disclosure includes all such variations and modifications. The disclosure
also includes all of the steps, features, compositions and materials
referred to or indicated in the specification, individually or
collectively and any and all combinations or any two or more of the steps
or features.

[0053] The present disclosure is not to be limited in scope by the
specific embodiments described herein, which are intended for the purpose
of exemplification only. Functionally equivalent products, compositions
and methods are clearly within the scope of the disclosure as described
herein.

[0054] The disclosure described herein may include one or more ranges of
values (e.g. size, concentration etc). A range of values will be
understood to include all values within the range, including the values
defining the range, and values adjacent to the range that lead to the
same or substantially the same outcome as the values immediately adjacent
to that value which defines the boundary to the range.

[0055] The entire disclosures of all publications (including patents,
patent applications, journal articles, laboratory manuals, books, or
other documents) cited herein are hereby incorporated by reference.
Inclusion does not constitute an admission is made that any of the
references constitute prior art or are part of the common general
knowledge of those working in the field to which this disclosure relates.

[0056] Throughout this specification, unless the context requires
otherwise, the word "comprise" or variations, such as "comprises" or
"comprising" will be understood to imply the inclusion of a stated
integer, or group of integers, but not the exclusion of any other
integers or group of integers. It is also noted that in this disclosure,
and particularly in the claims and/or paragraphs, terms such as
"comprises", "comprised", "comprising" and the like can have the meaning
attributed to it in US Patent law; e.g., they can mean "includes",
"included", "including", and the like.

[0057] "Therapeutically effective amount" as used herein with respect to
methods of treatment and in particular drug dosage, shall mean that
dosage that provides the specific pharmacological response for which the
drug is administered in a significant number of subjects in need of such
treatment. It is emphasized that "therapeutically effective amount,"
administered to a particular subject in a particular instance will not
always be effective in treating the diseases described herein, even
though such dosage is deemed a "therapeutically effective amount" by
those skilled in the art. It is to be further understood that drug
dosages are, in particular instances, measured as oral dosages, or with
reference to drug levels as measured in blood.

[0058] The term "inhibit" is defined to include its generally accepted
meaning which includes prohibiting, preventing, restraining, and
lowering, stopping, or reversing progression or severity, and such action
on a resultant symptom. As such the present disclosure includes both
medical therapeutic and prophylactic administration, as appropriate.

[0059] The term "grinding matrix" is defined as any substance that a
biologically active material can be or is combined with and milled the
abiraterone acetate. The terms "co-grinding matrix" and "matrix" are
interchangeable with "grinding matrix".

[0060] Throughout this specification, unless the context requires
otherwise, the phrase "dry mill" or variations, such as "dry milling,"
should be understood to refer to milling in at least the substantial
absence of liquids or fluids. If liquids are present, they are present in
such amounts that the contents of the mill retain the characteristics of
a dry powder.

[0061] "Flowable" means a powder having physical characteristics rendering
it suitable for further processing using typical equipment used for the
manufacture of pharmaceutical compositions and formulations.

[0062] Other definitions for selected terms used herein may be found
within the detailed description of the disclosure and apply throughout.
Unless otherwise defined, all other scientific and technical terms used
herein have the same meaning as commonly understood to one of ordinary
skill in the art to which the disclosure belongs.

[0063] The term "millable" means that the grinding matrix is capable of
being reduced in size under the dry milling conditions of the method of
the disclosure. In one embodiment of the disclosure, the milled grinding
matrix is of a comparable particle size to the abiraterone acetate. In
another embodiment of the disclosure the particle size of the matrix is
substantially reduced but not as small as the abiraterone acetate

[0064] Other definitions for selected terms used herein may be found
within the detailed description of the disclosure and apply throughout.
Unless otherwise defined, all other scientific and technical terms used
herein have the same meaning as commonly understood to one of ordinary
skill in the art to which the disclosure belongs.

[0065] Other aspects and advantages of the disclosure will become apparent
to those skilled in the art from a review of the ensuing description.

DRAWINGS

[0066] FIG. 1 is a graph depicting the size distribution of abiraterone
acetate in a milled arbiraterone acetate composition from Example 1 and
unmilled abiraterone acetate.

[0067] FIG. 2 is a graph depicting the dissolution of abiraterone acetate
in a milled arbiraterone acetate composition from Example 1 and unmilled
abiraterone acetate.

[0068] FIG. 3 is a graph depicting the dissolution of abiraterone acetate
in a milled arbiraterone acetate composition from Example 3 and unmilled
abiraterone acetate.

[0069] FIG. 4 is a graph depicting the size distribution of abiraterone
acetate in a milled arbiraterone acetate composition from Example 1 and
unmilled abiraterone acetate.

[0070] FIG. 5A is a graph depicting impurities detected over time in
milled DPI.

[0071] FIG. 5B is a graph depicting impurities detected over time in
tablets containing milled DPI

[0074] There are a wide range of techniques that can be utilized to
characterize the particle size of a material. Amongst these various
techniques, two types of measurements are most commonly used. Photon
correlation spectroscopy (PCS), also known as `dynamic light scattering`
(DLS) is commonly used to measure particles with a size less than 10
micron. Typically this measurement yields an equivalent hydrodynamic
radius often expressed as the average size of a number distribution. The
other common particle size measurement is laser diffraction which is
commonly used to measure particle size from 100 nm to 2000 micron. This
technique calculates a volume distribution of equivalent spherical
particles that can be expressed using descriptors such as the median
particle size or the % of particles under a given size.

[0075] For measurements made using a photo correlation spectroscopy
instrument, or an equivalent method known in the art, the term "number
average particle size" is defined as the average particle diameter as
determined on a number basis.

[0076] For measurements made using a laser diffraction the term "median
particle size" is defined as the median particle diameter as determined
on an equivalent spherical particle volume basis. Where the term median
is used, it is understood to describe the particle size that divides the
population in half such that 50% of the population on a volume basis is
greater than or less than this size. The median particle size is written
as: [D50] or D.sub.[50] or [D50], D50, D(0.50) or D[0.5] or similar.
As used herein [D50] or D.sub.[50] or [D50], D50, D(0.50) or D[0.5]
or similar shall be taken to mean median particle size.

[0077] The term "Dx of the particle size distribution" refers to the xth
percentile of the distribution on a volume basis; thus, D90 refers to the
90th percentile, D95 refers to the 95th percentile, and so
forth. Taking D90 as an example this can often be written as, [D90]
or D.sub.[90] or [D90], D(0.90) or D[0.9] or similar. With respect to the
median particle size and Dx an upper case D or lowercase d are
interchangeable and have the same meaning. Another commonly used way of
describing a particle size distribution measured by laser diffraction, or
an equivalent method known in the art, is to describe what % of a
distribution is under or over a nominated size. The term "percentage less
than" also written as "%<" is defined as the percentage, by volume, of
a particle size distribution under a nominated size--for example the
%<1000 nm. The term "percentage greater than" also written as "%>"
is defined as the percentage, by volume, of a particle size distribution
over a nominated size--for example the %>1000 nm.

[0078] For many of the materials subject to the methods of this disclosure
the particle size can be easily measured. Where the active material has
poor water solubility and the matrix it is milled in has good water
solubility the powder can simply be dispersed in an aqueous solvent. In
this scenario the matrix dissolves leaving the active material dispersed
in the solvent. This suspension can then be measured by techniques such
as PCS or laser diffraction.

[0079] Suitable methods to measure an accurate particle size where the
active material has substantive aqueous solubility or the matrix has low
solubility in a water based dispersant are outlined below.

[0080] 1. In
the circumstance where an insoluble matrix such as microcrystalline
cellulose prevents the measurement of the active material separation
techniques such as filtration or centrifugation could be used to separate
the insoluble matrix from the active material particles. Other ancillary
techniques would also be required to determine if any active material was
removed by the separation technique so that this could be taken into
account.

[0081] 2. In the case where the active material is too soluble
in water, other solvents could be evaluated for the measurement of
particle size. Where a solvent could be found that active material is
poorly soluble in but is a good solvent for the matrix a measurement
would be relatively straight forward. If such a solvent is difficult to
find another approach would be to measure the ensemble of matrix and
active material in a solvent (such as iso-octane) which both are
insoluble in. Then the powder would be measured in another solvent where
the active material is soluble but the matrix is not. Thus with a
measurement of the matrix particle size and a measurement of the size of
the matrix and active material together an understanding of the active
material particle size can be obtained.

[0082] 3. In some circumstances
image analysis could be used to obtain information about the particle
size distribution of the active material. Suitable image measurement
techniques might include transmission electron microscopy (TEM), scanning
electron microscopy (SEM), optical microscopy and confocal microscopy. In
addition to these standard techniques some additional technique would be
required to be used in parallel to differentiate the active material and
matrix particles. Depending on the chemical makeup of the materials
involved possible techniques could be elemental analysis, Raman
spectroscopy, FTIR spectroscopy or fluorescence spectroscopy.

Improving the Dissolution Profile

[0083] The process results in the abiraterone acetate having an improved
dissolution profile. An improved dissolution profile has significant
advantages including the improvement of bioavailability of the
abiraterone acetate in vivo. In some embodiments, the improved
dissolution profile is observed in vitro. Alternatively, the improved
dissolution profile is observed in vivo by the observation of an improved
bioavailability profile. Standard methods for determining the dissolution
profile of a material in vitro are available in the art. A suitable
method to determine an improved dissolution profile in vitro may include
determining the concentration of the sample material in a solution over a
period of time and comparing the results from the sample materialto a
control sample. An observation that peak solution concentration for the
sample material was achieved in less time than the control sample would
indicate (assuming it is statistically significant), that the sample
material has an improved dissolution profile. The measurement sample is
herein defined as the mixture of abiraterone acetate with grinding matrix
and/or other additives that has been subject to the processes of the
disclosure described here. Herein a control sample is defined as a
physical mixture (not subject to the processes described in this
disclosure) of the components in the measurement sample with the same
relative proportions of active, matrix and/or additive as the measurement
sample. For the purposes of the dissolution testing a prototype
formulation of the measurement sample could also be used. In this case
the control sample would be formulated in the same way. Standard methods
for determining the improved dissolution profile of a material in vivo
are available in the art. A suitable method to determine an improved
dissolution profile in a human may be after delivering the dose to
measure the rate of active material absorption by measuring the plasma
concentration of the sample compound over a period of time and comparing
the results from the sample compound to a control. An observation that
peak plasma concentration for the sample compound was achieved in less
time than the control would indicate (assuming it is statistically
significant) that the sample compound has improved bioavailability and an
improved dissolution profile. In some embodiments, the improved
dissolution profile is observed at a relevant gastrointestinal pH, when
it is observed in vitro. In some embodiments, the improved dissolution
profile is observed at a pH which is favourable at indicating
improvements in dissolution when comparing the measurement sample to the
control compound. Suitable methods for quantifying the concentration of a
compound in an in vitro sample or an in vivo sample are widely available
in the art. Suitable methods could include the use of spectroscopy or
radioisotope labeling.

Crystallization Profile

[0084] Methods for determining the crystallinity profile of the
abiraterone acetate are widely available in the art. Suitable methods may
include X-ray diffraction, differential scanning calorimetry, Raman or IR
spectrocopy.

Amorphicity Profile

[0085] Methods for determining the amorphous content of the abiraterone
acetate are widely available in the art. Suitable methods may include
X-ray diffraction, differential scanning calorimetry, Raman or IR
spectroscopy.

Grinding Matrix

[0086] As will be described subsequently, selection of an appropriate
grinding matrix affords particular advantageous applications of the
method of the present disclosure.

[0087] Again, as will be described subsequently, a highly advantageous
aspect of the present disclosure is that certain grinding matrixes
appropriate for use in the method of the disclosure are also appropriate
for use in a medicament. The present disclosure encompasses methods for
the production of a medicament incorporating both the abiraterone acetate
and the grinding matrix or in some cases the abiraterone acetate and a
portion of the grinding matrix, medicaments so produced, and methods of
treatment using the medicament. The medicament may include only the
milled abiraterone acetate together with the milled grinding matrix or,
more preferably, the milled abiraterone acetate and milled grinding
matrix may be combined with one or more pharmaceutically acceptable
carriers, as well as any desired excipients or other like agents commonly
used in the preparation of medicaments.

[0088] In some cases at least one component of the grinding matrix is
harder than the abiraterone acetate, and is thus capable of reducing the
particle size of the abiraterone acetate under the dry milling conditions
of the disclosure. Again without wishing to be bound by theory, under
these circumstances it is believed that the millable grinding matrix
affords the advantage of the present disclosure through a second route,
with the smaller particles of grinding matrix produced under the dry
milling conditions enabling greater interaction with the abiraterone
acetate.

[0089] The quantity of the grinding matrix relative to the quantity of
abiraterone acetate, and the extent of physical degradation of the
grinding matrix, is sufficient to inhibit re-agglomeration of the
particles of the active material In some embodiments, the quantity of the
grinding matrix relative to the quantity of abiraterone acetate, and the
extent of size reduction of the grinding matrix, is sufficient to inhibit
re-agglomeration of the particles of the active material. As detailed
above, the grinding matrix can include one or more anti-oxidants and/or
one or more sequestering agents.

[0090] In some embodiments, the grinding matrix has a low tendency to
agglomerate during dry milling. While it is difficult to objectively
quantify the tendency to agglomerate during milling, it is possible to
obtain a subjective measure by observing the level of "caking" of the
grinding matrix on the milling bodies and the milling chamber of the
media mill as dry milling progresses.

[0091] The grinding matrix may be an inorganic or organic substance.

Milling Bodies

[0092] In the method of the present disclosure, the milling bodies are
preferably chemically inert and rigid. The term "chemically-inert", as
used herein, means that the milling bodies do not react chemically with
the abiraterone acetate or the grinding matrix.

[0093] As described above, the milling bodies are essentially resistant to
fracture and erosion in the milling process.

[0094] The milling bodies are desirably provided in the form of bodies
which may have any of a variety of smooth, regular shapes, flat or curved
surfaces, and lacking sharp or raised edges. For example, suitable
milling bodies can be in the form of bodies having ellipsoidal, ovoid,
spherical or right cylindrical shapes. In some embodiments, the milling
bodies are provided in the form of one or more of beads, balls, spheres,
rods, right cylinders, drums or radius-end right cylinders (i.e., right
cylinders having hemispherical bases with the same radius as the
cylinder).

[0095] Depending on the nature of the abiraterone acetate and the grinding
matrix, the milling bodies desirably have an effective mean particle
diameter (i.e. "particle size") between about 0.1 and 30 mm, more
preferably between about 1 and about 15 mm, still more preferably between
about 3 and 10 mm.

[0096] The milling bodies may comprise various substances such as ceramic,
glass, metal or polymeric compositions, in a particulate form. Suitable
metal milling bodies are typically spherical and generally have good
hardness (i.e. RHC 60-70), roundness, high wear resistance, and narrow
size distribution and can include, for example, balls fabricated from
type 52100 chrome steel, type 304, 316 or 440 C stainless steel or type
1065 high carbon steel.

[0097] Ceramics, for example, can be selected from a wide array of
ceramics desirably having sufficient hardness and resistance to fracture
to enable them to avoid being chipped or crushed during milling and also
having sufficiently high density. Suitable densities for milling bodies
can range from about 1 to 15 g/cm3, preferably from about 1 to 8
g/cm3. Ceramics can be selected from steatite, aluminum oxide,
zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide,
magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide,
cobalt-stabilized tungsten carbide, and the like, as well as mixtures
thereof.

[0098] Glass milling bodies are spherical (e.g. beads), have a narrow size
distribution, are durable, and include, for example, lead-free soda lime
glass and borosilicate glass. Polymeric milling bodies are preferably
substantially spherical and can be selected from a wide array of
polymeric resins having sufficient hardness and friability to enable them
to avoid being chipped or crushed during milling, abrasion-resistance to
minimize attrition resulting in contamination of the product, and freedom
from impurities such as metals, solvents, and residual monomers.

[0099] Milling bodies can be formed from polymeric resins. Polymeric
resins, for example, can be selected from crosslinked polystyrenes, such
as polystyrene crosslinked with divinylbenzene, styrene copolymers,
polyacrylates such as polymethylmethacrylate, polycarbonates,
polyacetals, vinyl chloride polymers and copolymers, polyurethanes,
polyamides, high density polyethylenes, polypropylenes, and the like. The
use of polymeric milling bodies to grind materials down to a very small
particle size (as opposed to mechanochemical synthesis) is disclosed, for
example, in U.S. Pat. Nos. 5,478,705 and 5,500,331. Polymeric resins
typically can have densities ranging from about 0.8 to 3.0 g/cm3.
Higher density polymeric resins are generally preferred. Alternatively,
the milling bodies can be composite bodies comprising dense core bodies
having a polymeric resin adhered thereon. Core particles can be selected
from substances known to be useful as milling bodies, for example, glass,
alumina, zirconia silica, zirconium oxide, stainless steel, and the like.
Core substances have densities greater than about 2.5 g/cm3.

[0100] In one embodiment of the disclosure, the milling bodies are formed
from a ferromagnetic substance, thereby facilitating removal of
contaminants arising from wear of the milling bodies by the use of
magnetic separation techniques.

[0101] Each type of milling body has its own advantages. For example,
metals have the highest specific gravities, which increase grinding
efficiency due to increased impact energy. Metal costs range from low to
high, but metal contamination of final product can be an issue. Glasses
are advantageous from the standpoint of low cost and the availability of
small bead sizes as low as 0.004 mm. However, the specific gravity of
glasses is lower than other bodies and significantly more milling time is
required. Finally, ceramics are advantageous from the standpoint of low
wear and contamination, ease of cleaning, and high hardness.

Dry Milling

[0102] In the dry milling process of the present disclosure, the
abiraterone acetate and grinding matrix, in the form of crystals,
powders, or the like, are combined in suitable proportions with the
plurality of milling bodies in a milling chamber that is mechanically
agitated (i.e. with or without stirring) for a predetermined period of
time at a predetermined intensity of agitation. Typically, a milling
apparatus is used to impart motion to the milling bodies by the external
application of agitation, whereby various translational, rotational or
inversion motions or combinations thereof are applied to the milling
chamber and its contents, or by the internal application of agitation
through a rotating shaft terminating in a blade, propeller, impeller or
paddle or by a combination of both actions.

[0103] During milling, motion imparted to the milling bodies can result in
application of shearing forces as well as multiple impacts or collisions
having significant intensity between milling bodies and particles of the
abiraterone acetate and grinding matrix. The nature and intensity of the
forces applied by the milling bodies to the abiraterone acetate and the
grinding matrix is influenced by a wide variety of processing parameters
including: the type of milling apparatus; the intensity of the forces
generated, the kinematic aspects of the process; the size, density,
shape, and composition of the milling bodies; the weight ratio of the
abiraterone acetate and grinding matrix mixture to the milling bodies;
the duration of milling; the physical properties of both the abiraterone
acetate and the grinding matrix; the atmosphere present during
activation; and others.

[0104] Advantageously, the media mill is capable of repeatedly or
continuously applying mechanical compressive forces and shear stress to
the abiraterone acetate and the grinding matrix. Suitable media mills
include but are not limited to the following: high-energy ball, sand,
bead or pearl mills, basket mill, planetary mill, vibratory action ball
mill, multi-axial shaker/mixer, stirred ball mill, horizontal small media
mill, multi-ring pulverizing mill, and the like, including small milling
media. The milling apparatus also can contain one or more rotating
shafts.

[0105] In a form of the disclosure, the dry milling is performed in a ball
mill. Throughout the remainder of the specification reference will be
made to dry milling being carried out by way of a ball mill. Examples of
this type of mill are attritor mills, nutating mills, tower mills,
planetary mills, vibratory mills and gravity-dependent-type ball mills.
It will be appreciated that dry milling in accordance with the method of
the disclosure may also be achieved by any suitable means other than ball
milling. For example, dry milling may also be achieved using jet mills,
rod mills, roller mills or crusher mills.

[0106] In some cases, the particle size of the abiraterone acetate prior
to dry milling according to the methods described herein in less than
about 1000 μm, as determined by sieve analysis. If the particle size
of the abiraterone acetate is greater than about 1000 μm, then it is
preferred that the particles of the abiraterone acetate substrate be
reduced in size to less than 1000 μm using another standard milling
method prior to dry milling according to the methods described herein.

Agglomerates of Abiraterone Acetate after Processing

[0107] Agglomerates comprising particles of abiraterone acetate having a
particle size within the ranges specified herein, should be understood to
fall within the scope of the present disclosure, regardless of whether
the agglomerates exceed the ranges specified above.

Processing Time

[0108] In some embodiments, the abiraterone acetate and the grinding
matrix are dry milled for the shortest time necessary to minimise any
possible contamination from the media mill and/or the plurality of
milling bodies. This time varies greatly, depending on the abiraterone
acetate and the grinding matrix, and may range from as short as 1 minute
to several hours.

[0109] Suitable rates of agitation and total milling times are adjusted
for the type and size of milling apparatus as well as the milling media,
the weight ratio of the abiraterone acetate and grinding matrix mixture
to the plurality of milling bodies, the chemical and physical properties
of the abiraterone acetate and grinding matrix, and other parameters that
may be optimized empirically.

[0110] In some embodiments, the grinding matrix (the materials milled
together with abiraterone acetate) is not separated from the abiraterone
acetate but is maintained with the abiraterone acetate in the final
product. In some embodiments the grinding matrix is considered to be
Generally Regarded as Safe (GRAS) for pharmaceutical products.

[0111] In an alternative aspect, the grinding matrix is separated from the
abiraterone acetate. In one aspect, where the grinding matrix is not
fully milled, the unmilled grinding matrix is separated from the
abiraterone acetate. In a further aspect, at least a portion of the
milled grinding matrix is separated from the abiraterone acetate.

[0112] Any portion of the grinding matrix may be removed, including but
not limited to 10%, 25%, 50%, 75%, or substantially all of the grinding
matrix.

[0113] In some embodiments of the disclosure, a significant portion of the
milled grinding matrix may comprise particles of a size similar to and/or
smaller than the particles comprising the abiraterone acetate. Where the
portion of the milled grinding matrix to be separated from the particles
comprising the abiraterone acetate comprises particles of a size similar
to and/or smaller than the particles comprising the abiraterone acetate,
separation techniques based on size distribution are inapplicable. In
these circumstances, the method of the present disclosure may involve
separation of at least a portion of the milled grinding matrix from the
abiraterone acetate by techniques including but not limited to
electrostatic separation, magnetic separation, centrifugation (density
separation), hydrodynamic separation, and froth flotation.
Advantageously, the step of removing at least a portion of the milled
grinding matrix from the abiraterone acetate may be performed through
means such as selective dissolution, washing, or sublimation.

[0114] An advantageous aspect of the disclosure would be the use of
grinding matrix that has two or more components where at least one
component is water soluble and at least one component has low solubility
in water. In this case washing can be used to remove the matrix component
soluble in water leaving the abiraterone acetate dispersed in the
remaining matrix components.

[0115] In a highly advantageous aspect of the disclosure the matrix with
low solubility is a functional excipient.

[0116] A highly advantageous aspect of the present disclosure is that
certain grinding matrixes appropriate for use in the method of the
disclosure are also pharmaceutically acceptable and thus appropriate for
use in a medicament. Where the method of the present disclosure does not
involve complete separation of the grinding matrix from the abiraterone
acetate, the present disclosure encompasses methods for the production of
a medicament incorporating both the abiraterone acetate and at least a
portion of the milled grinding matrix, medicaments so produced and
methods of treatment of an animal, including man, using a therapeutically
effective amount of said abiraterone acetate by way of said medicaments.

Abiraterone Acetate and Compositions

[0117] The present disclosure encompasses pharmaceutically acceptable
materials produced according to the methods of the present disclosure,
compositions including such materials, including compositions comprising
such materials together with the grinding matrix with or without milling
aids, facilitating agents, with at least a portion of the grinding matrix
or separated from the grinding matrix.

[0118] The pharmaceutically acceptable materials within the compositions
of the disclosure are present at a concentration of between about 0.1%
and about 99.0% by weight. In some embodiments, the concentration of
pharmaceutically acceptable materials within the compositions will be
about 5% to about 80% by weight, e.g., about 10% to about 50% by weigh.
Desirably, the concentration will be in the range of about 10 to 15% by
weight, 15 to 20% by weight, 20 to 25% by weight, 25 to 30% by weight, 30
to 35% by weight, 35 to 40% by weight, 40 to 45% by weight, 45 to 50% by
weight, 50 to 55% by weight, 55 to 60% by weight, 60 to 65% by weight, 65
to 70% by weight, 70 to 75% by weight or 75 to 80% by weight for the
composition prior to any later removal (if desired) of any portion of the
grinding matrix. Where part or all of the grinding matrix has been
removed, the relative concentration of pharmaceutically acceptable
materials in the composition may be considerably higher depending on the
amount of the grinding matrix that is removed. For example, if all of the
grinding matrix is removed the concentration of particles in the
preparation may approach 100% by weight (subject to the presence of
facilitating agents).

Medicaments

[0119] The medicaments of the present disclosure may include the
pharmaceutically acceptable material, optionally together with the
grinding matrix or at least a portion of the grinding matrix, with or
without milling aids, facilitating agents, combined with one or more
pharmaceutically acceptable carriers, as well as other agents commonly
used in the preparation of pharmaceutically acceptable compositions.

[0120] As used herein "pharmaceutically acceptable carrier" includes any
and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the like
that are physiologically compatible. In some embodiments, the carrier is
suitable for parenteral administration, intravenous, intraperitoneal,
intramuscular, sublingual, pulmonary, transdermal or oral administration.
Pharmaceutically acceptable carriers include sterile aqueous solutions or
dispersions and sterile powders for the extemporaneous preparation of
sterile injectable solutions or dispersion. The use of such media and
agents for the manufacture of medicaments is well known in the art.
Except insofar as any conventional media or agent is incompatible with
the pharmaceutically acceptable material, use thereof in the manufacture
of a pharmaceutical composition according to the disclosure is
contemplated.

[0121] Pharmaceutical acceptable carriers according to the disclosure may
include one or more of the following examples:

[0123] (2) binding agents such as
various celluloses and cross-linked polyvinylpyrrolidone,
microcrystalline cellulose; and or

[0124] (3) filling agents such as
lactose monohydrate, lactose anhydrous, microcrystalline cellulose and
various starches; and or

[0125] (4) lubricating agents such as agents
that act on the flowability of the powder to be compressed, including
colloidal silicon dioxide, talc, stearic acid, magnesium stearate,
calcium stearate, silica gel; and or

[0126] (5) sweeteners such as any
natural or artificial sweetener including sucrose, xylitol, sodium
saccharin, cyclamate, aspartame, and acesulfame K; and or

[0127] (6)
flavouring agents; and or

[0128] (7) preservatives such as potassium
sorbate, methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols such as
ethyl or benzyl alcohol, phenolic chemicals such as phenol, or
quarternary compounds such as benzalkonium chloride; and or

[0129] (8)
buffers; and or

[0130] (9) Diluents such as pharmaceutically acceptable
inert fillers, such as microcrystalline cellulose, lactose, dibasic
calcium phosphate, saccharides, and/or mixtures of any of the foregoing;
and or

[0131] (10) wetting agents such as corn starch, potato starch,
maize starch, and modified starches, and mixtures thereof; and or

[0132]
(11) disintegrants; such as croscarmellose sodium, crospovidone, sodium
starch glycolate, and or

[0135] Actual dosage levels of abiraterone acetate disclosure may be
varied in accordance with the nature of the abiraterone acetate, as well
as the potential increased efficacy due to the advantages of providing
and administering the abiraterone acetate (e.g., increased solubility,
more rapid dissolution, increased surface area of the abiraterone
acetate, etc.). Thus as used herein "therapeutically effective amount"
will refer to an amount of abiraterone acetate required to effect a
therapeutic response in an animal. Amounts effective for such a use will
depend on: the desired therapeutic effect; the route of administration;
the potency of the abiraterone acetate; the desired duration of
treatment; the stage and severity of the disease being treated; the
weight and general state of health of the patient; and the judgment of
the prescribing physician.

Pharmacokinetic Properties of Abiraterone Acetate Compositions

Fast Onset of Activity

[0136] In some embodiments, the abiraterone acetate compositions of the
disclosure are rapidly absorbed. In one example, following administration
the abiraterone acetate compositions of the disclosure comprising
abiraterone acetate have a Tmax of less than about 2 hours, less
than about 1.75 hours, less than about 1.5 hours, less than about 1.25
hours, less than about 1.0 hours, less than about 50 minutes, less than
about 40 minutes, or less than about 30 minutes.

Increased Bioavailability

[0137] The abiraterone acetate compositions of the disclosure exhibit
increased bioavailability (AUC) and require smaller doses as compared to
prior conventional compositions administered at the same dose (e.g.,
Zytiga®). Any drug composition can have adverse side effects. Thus,
lower doses of drugs which can achieve the same or better therapeutic
effects as those observed with larger doses of conventional compositions
are desired. Such lower doses can be realized with the compositions of
the disclosure because the greater bioavailability observed with the
compositions as compared to conventional drug formulations means that
smaller doses of drug are required to obtain the desired therapeutic
effect.

The Pharmacokinetic Profiles of the Compositions of the Disclosure are
Less Substantially Affected by the Fed or Fasted State of the Subject
Ingesting the Compositions

[0138] The disclosure encompasses abiraterone acetate compositions wherein
the pharmacokinetic profile of the composition is less substantially
affected by the fed or fasted state of a subject ingesting the
composition compared to Zytiga®. This means that there is a less
substantial difference in the quantity of composition or the rate of
composition absorption when the compositions are administered in the fed
versus the fasted state. Thus, the compositions of the disclosure
substantially reduce the effect of food on the pharmacokinetics of the
composition compared to Zytiga®.

[0139] Any standard pharmacokinetic protocol can be used to determine
blood plasma concentration profile in humans following administration of
a composition, and thereby establish whether that composition meets the
pharmacokinetic criteria set out herein. For example, a randomized
single-dose crossover study can be performed using a group of healthy
adult human subjects. The number of subjects should be sufficient to
provide adequate control of variation in a statistical analysis, and is
typically about 10 or greater, although for certain purposes a smaller
group can suffice. Each subject receives by oral administration at time
zero a single dose (e.g., 100 mg) of a test formulation of composition,
normally at around 8 am following an overnight fast. The subjects
continue to fast and remain in an upright position for about 4 hours
after administration of the composition. Blood samples are collected from
each subject prior to administration (e.g., 15 minutes) and at several
intervals after administration. For the present purpose it is to take
several samples within the first hour, and to sample less frequently
thereafter. Illustratively, blood samples could be collected at 15, 30,
45, 60, and 90 minutes after administration, then every hour from 2 to 10
hours after administration. Additional blood samples may also be taken
later, for example at 12 and 24 hours after administration. If the same
subjects are to be used for study of a second test formulation, a period
of at least 7 days should elapse before administration of the second
formulation. Plasma is separated from the blood samples by centrifugation
and the separated plasma is analyzed for composition by a validated high
performance liquid chromatography (HPLC) or liquid chromatography mass
spectrometry (LCMS) procedure. Plasma concentrations of composition
referenced herein are intended to mean total concentrations including
both free and bound composition.

[0140] Any formulation giving the desired pharmacokinetic profile is
suitable for administration according to the present methods. Exemplary
types of formulations giving such profiles are liquid dispersions and
solid dose forms of composition. If the liquid dispersion medium is one
in which the composition has very low solubility, the particles are
present as suspended particles.

[0141] Medicaments of the disclosure can be administered to animals,
including man, in any pharmaceutically acceptable manner, such as orally,
rectally, pulmonary, intravaginally, locally (powders, ointments or
drops), transdermal, parenteral administration, intravenous,
intraperitoneal, intramuscular, sublingual or as a buccal or nasal spray.

[0142] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, pellets, and granules. Further, incorporating
any of the normally employed excipients, such as those previously listed,
and generally 5-95% of the biologically active agent, and more preferably
at a concentration of 10%-75% will form a pharmaceutically acceptable
non-toxic oral composition.

[0143] However, if the abiraterone acetate is to be utilized in a liquid
suspension, the particles comprising the abiraterone acetate may require
further stabilization once the solid carrier has been substantially
removed to ensure the elimination, or at least minimisation of particle
agglomeration.

[0146] The results indicate that under the conditions studied, only
approximately 10% of the unmilled abiraterone acetate (25 mg) is
dissolved after one hour, while 100% of the nanoparticulate abiraterone
acetate the dissolution (25 mg) is dissolved within approximately 10
minutes (FIG. 2).

[0148] Milled powder samples from Example 3 were analyzed by adding 26 mg
of milled material (6 mg of abiraterone acetate) to 5 ml of 0.1% w/w
aqueous polyvinylpyrrolidone solution (PVP; BASF Kollidon® 30), then
sonicating with an external sonication horn (Branson Digital
Sonifier®) for 5 seconds at 20% amplitude followed by a 15 second
pause. This cycle was continued until the total sonication time reached
one minute. This suspension was then added dropwise to the sample cell of
a Malvern Mastersizer 3000 particle size analyzer (Malvern Hydro MV pump
unit) containing 125 ml of 0.1% PVP. The sample was then allowed to stir
for 5 minutes prior to taking measurements. Data from the final
measurements are presented in Table 1 and depicted graphically in FIG. 3.

[0149] For comparison, the particle size distribution of unmilled
abiraterone acetate (raw drug substance) was also determined. The
measurement conditions were similar as described above with the exception
that the unmilled abiraterone acetate was added directly to the Malvern
Hydro MV pump unit containing 130 ml of 0.1% PVP. 26 mg of unmilled
abiraterone acetate had to be added directly to the Malvern pump unit in
order to obtain obscuration values similar to that of the milled
material. The abiraterone acetate was then subjected to 1 minute of bath
sonication at 100% amplitude. The sample was then allowed to stir for 5
minutes prior to taking measurements. The data from these measurements
are presented in Table 1 and depicted graphically in FIG. 3. The results
indicate that the milled abiraterone acetate material contained fine
particle drug substance and that the size of the drug particles in the
milled abiraterone acetate material was substantially smaller (greater
than 10 times) than in the unmilled material. No fine particle
abiraterone acetate was measured in the unmilled drug sample.

[0151] Dissolution behavior of the milled abiraterone acetate powder blend
prepared in Example 3 was determined using an automated Sotax AT7 Smart
dissolution testing unit fitted with a Thermo Fisher Scientific UV
visible spectrometer (Model # EV0300 PC). The dissolution media was a
0.01 N HCl (pH=2) solution. The USP dissolution vessels were filled with
1000 ml of media and equilibrated to 37° C. The dissolution
settings were according to USP type II apparatus with stirrer speed at
100 rpm. Two inline filters were utilized in series with pore sizes of
0.7 μm and 2.7 μm. The absorbance was measured at λ=236 nm.
Dissolution studies were performed by adding duplicate samples of milled
and unmilled abiraterone acetate powder blends directly to the
dissolution media. The unmilled powder blend was identical in composition
to the milled powder blend but was not processed in the mill. An
abiraterone acetate dose of 100 mg was used for milled and unmilled
samples which corresponded to a total powder weight of 500.0 mg. For the
powder dissolution studies, measurements were taken at 2, 4, 6, 8, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110 and 120
minutes. The dissolution results are plotted as percent of abiraterone
acetate dissolved. The results of this comparative study are presented in
Table 2 and illustrated graphically in FIG. 4. The results show that
milled nanoparticulate abiraterone acetate dissolved more rapidly and to
a greater percentage than the unmilled material.

[0152] When abiraterone acetate particles larger than several microns in
diameter was dry milled with lactose monohydrate and sodium lauryl
sulfate then tested for impurities, 0.4-0.6% total impurities was
detected (% AUC). When this milled drug product intermediate (DPI) was
further processed into tablets, the level of impurities was found to be
higher, about 0.5-1.1%. Stability testing showed that the impurities grew
at 25° C./60% RH and at 40° C./75% RH, but did not grow at
2-8° C. In addition, impurity growth in the tablets was faster
than that in the milled DPI. FIG. 5A (diamonds, 5° C.; triangles,
25° C./60% RH; and crosses, 40° C./75% RH) and FIG. 5B
(diamonds, 5° C.; squares, 25° C./60% RH and triangles,
40° C./75% RH) provide an overview of the impurity levels in lots
of milled DPI and tablets, respectively upon accelerated stability
testing. Tablets packaged with a nitrogen purge and stored refrigerated
had an acceptably low level of impurities, but it is desirable to have
formulation that can be stored under ambient conditions.

[0153] The observed increase in impurities was compared to Zytiga®,
and the increase in impurities seen with the DPI and tablets containing
fine powder abiraterone acetate was found to be greater than that
observed with Zytiga®.

[0154] The higher level of in impurities in tablets containing fine
particle abiraterone acetate compared to Zytiga® could arise from a
number of sources, including, but not limited to: greater surface area of
the API, higher proportion of excipients, and difference in excipients.

[0155] As part of the analysis of impurity growth, the impact on impurity
level of various excipients useful for tablet preparation was examined by
blending the DPI with various excipients and heating for 4 hours at
80° C. Microcrystalline cellulose (MCC), sodium lauryl sulfate
(SLS), crosscarmellose sodium (CCS), sodium steryl fumarate (SSF),
magnesium stetarate and hydrogentate vegetable oil were found to be
associated with a lower level of impurity growth than
pregelatiniaedstrach, spray dried lactose, poloxamer 188, crosspovidone,
sodium starch glycolate. However, a mixture of MCC, SLS, CCS and SSF
appeared to have a more detrimental impact on stability than might be
suggested by the individual impact of the components.

[0156] Additional studies indicated that the observed impurities appear to
be degradation products of abiraterone acetate. Analysis if the API prior
to size reduction showed essentially no degradation after 4 hours at
80° C., and minimal impurity growth when unmilled API is mixed
with the excipients and heated. Further studies were conducted and it was
concluded that degradation is not due to simply an interaction with the
excipients or milling alone, but a combined effect.

Example 5

Milling with Antioxidant or Sequestering Agent

[0157] Dry milling of abiraterone acetate was carried out in the presence
of lactose monohydrate and sodium lauryl sulfate and various antioxidants
and/or sequestering agents. Thus, in one study the dry milling also
included a combination of ascorbic acid and fumaric acid or a combination
of butylated Hydroxyanisole (BHA) and butylated Hydroxytoluene (BHT).
This study produced DPI Formula Ascorbic/Fumaric and DPI Formula BHA/BHT,
as shown in Table 3. Both DPI Formula contained abiraterone acetate
having a [D90] below 1,000 nm and thus contain fine particle abiraterone
acetate

[0158] The stability of the two DPI Formula in Table 3 were tested under
accelerated conditions (4 hrs at 80° C.). For DPI Formula
Ascorbic/Fumaric, total impurities grew from 0.23 to only 0.80. For DPI
Formula BHA/BHT, total impurities did not grow (0.38 both before and
after 4 hrs at 80° C.). In contrast, a DPI Formula in which
abiraterone acetate was dry milled with only lactose monohydrate and
sodium lauryl sulfate (no antioxidant or sequestering agent), impurities
grew from 1.63 initially to 3.86 after 4 hrs at 80° C.

[0159] The two different DPI Formulas were used to prepare two different
corresponding tablet Formula as detailed in Table 4 by adding the
indicated excipients to the DPI Formula, dry granulating and tableting.

[0160] The stability of the two Tablets Formula was tested under
accelerated conditions (4 hrs at 80° C.). In for Tablet Formula
Ascorbic/Fumaric total impurities grew from 0.31 to only 0.38. For Tablet
Formula BHA/BHT total impurities grew from 0.41 to only 0.44. This
demonstrates that the addition of antioxidants and/or sequestering agent
during milling can dramatically improve stability.

[0161] The dissolution rate of the abiraterone acetate in the Tablet
Ascorbic/Fumaric and Tablet Formula BHA/BHT was tested using USP
Apparatus II at 75 rpm (900 ml of pH 4.5 phosphate buffer (0.1% SLS)).
Also tested was a similar formulation in which neither BHT/BHA or fumaric
acid/ascorbic acid was present during milling (Tablet Formula 3). As
shown in FIG. 6 (triangles, Tablet Formula 3; squares, Tablet Formula
BHA/BHT; diamonds, Tablet Formula ascorbic/fumaric), for all three types
of tablets, 80%-90% of the abiraterone acetate dissolved within 10
minutes.

[0162] In order to compare the dissolution rate to a conventional
abiraterone acetate formulation, a 250 mg Zytiga tablet, cut down to an
equivalent 100 mg weight was tested under the dissolution conditions
described above alongside Tablet Formula without antioxidants or
sequestering agent. As can be seen in FIG. 7 (diamonds, 100 mg Zytiga
tablet fragment; squares Tablet Formula 3), the Tablet Formula without
antioxidants or sequestering agent, containing fine particle abiraterone
acetate dissolved far more rapidly than the 100 mg portion of the Zytiga
tablet.